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The inheritance of gene expression patterns is dependent on epigenetic regulation, but the establishment and maintenance of epigenetic landscapes during T cell differentiation are incompletely understood. Here we show that two stage-specific  Cd4 cis -elements, the previously characterized enhancer E4p and a novel enhancer E4m, coordinately promote  Cd4  transcription in mature thymic MHC-II-specific T cells, in part through the canonical Wnt pathway. Specifically, E4p licenses E4m to orchestrate DNA demethylation by TET1 and TET3, which in turn poises the  Cd4  locus for transcription in peripheral T cells.  Cd4  locus demethylation is important for subsequent  Cd4  transcription in activated peripheral T cells wherein these  cis -elements become dispensable. By contrast, in developing thymocytes the loss of TET1/3 does not affect  Cd4  transcription, highlighting an uncoupled event between transcription and epigenetic modifications. Together our findings reveal an important function for thymic  cis- elements in governing gene expression in the periphery via a heritable epigenetic mechanism.

Stage-specific epigenetic regulation of CD4 expression by coordinated enhancer elements during T cell development